1. Field of the Invention
The present invention relates to pharmaceutical compositions containing a synergistic amount of at least one bone morphogenetic protein (BMP) and a synergistic amount of at least one pyrrolidone optionally in a pharmaceutically acceptable carrier, such as a biodegradable polymer. The present invention further relates to methods of treating orthopaedic and dental, including periodontal, diseases by simultaneously administering a synergistic amount of at least one bone morphogenetic protein (BMP) and a synergistic amount of at least one pyrrolidone optionally in a pharmaceutically acceptable carrier to patients in need of such treatment.
2. Description of the Related Art
In the last decade guided bone regeneration (GBR) has been introduced as a predictable and effective method for enhancing bone healing, and in particular in conjunction with the placement of dental implants GBR is a clinically well-documented and successful procedure [Dahlin, C., et al., Int J Periodontics Restorative Dent 11 (1991) 273–281; Hämmerle, C. H. and Karring, T., Periodontol 2000 17 (1998) 151–175; Nyman, S. R. and Lang, N. P. Periodontol 2000 4 (1994) 109–118]. In GBR, a membrane serves as a barrier for the connective tissue and maintains an open space for the time bone needs to fill it up.
An acceleration of this bone filling process can be achieved by the principle of osteoconduction, if the empty space is filled with porous materials, which serve as a scaffold for the newly formed bone [Reddi, H., Cytokine & Growth Factor Reviews 8 (1997) 11–20]. Alternatively, bone repair can be accelerated by osteoinduction, which involves the application of appropriate growth factors capable to differentiate mesenchymal stem cells to osteoblasts [Wozney, J. M. and Rosen, V., Clin Orthop Rel Res 346 (1998) 26–37].
The most useful growth factors in osteoinduction are bone morphogenetic proteins (BMPs), which are differentiation factors and have been isolated based on their ability to induce bone formation [Wozney, J. M., et al., Science 242 (1988) 1528–1534]. They build the BMP-family with more than thirty members belonging to the TGF-β-super-family. The BMP-family is divided to subfamilies including the BMPs, such as BMP-2 and BMP-4, osteogenic proteins (Ops), such as OP-1 or BMP-7, OP-2 or BMP-8, BMP-5, BMP-6 or Vgr-1, cartilage-derived morphogenetic proteins (CDMPs), such as CDMP-1 or BMP-14 or GDF-5, growth/differentiation factors (GDFs), such as GDF-1, GDF-3, GDF-8, GDF-9, GDF-11 or BMP-11, GDF-12 and GDF-14, and other subfamilies, such as BMP-3 or osteogenin, BMP-9 or GDF-2, and BMP10 (Reddi et al., 1997, supra).
Especially in animal models the BMPs have proved to be powerful inducers of bone formation and repair. However, due to the instant degradation of the BMPs upon contact with body fluids and the strong morphogenetic action of the BMPs, un-physiologically high doses of the BMPs are needed for the osteoinductive bioactivity [Weber, F. E., et al., Int J Oral Maxillofac Surg 31 (2002) 60–65; Rose, F. R. A. and Oreffo, R. O. C. Biochem Biophys Res Com 292 (2002) 1–7]. Topical administration routes must be used, which makes the choice of the carrier system critical, and suitable carrier systems are currently not available. Since the BMPs are usually produced with recombinant techniques and thus are expensive and available only in limited amounts, the BMPs, despite the acknowledged effect, have had no impact on the medical treatment of patients and they are not clinically applied at present.
Biodegradable (also referred to as resorbable, absorbable, and erodible) polymers are at present the material of choice for controlled-release systems, including those implantable into the patients to be treated due to their transient foreign-body reactions and their ability to regenerate tissues (see, for instance, The Biomedical Engineering Handbook, Bronzino, J. D., Ed., CRC Press, Boca Raton, 2000, chapter 41, pages 41–1 to 41–22). The most studied biodegradable polymers include poly(lactic acid)s (PLA), poly(lactide-co-glycolide)-poly(ethyleneglycol) (PLG-PEG) copolymers, PLG-PGA copolymers, and like. However, synthetic biodegradable polymers are rigid and lack the flexibility needed to be applicable for instance in GBR, especially in dental GBR.
In U.S. patent application Ser. No. 10/006,800 the Applicants disclose that the rigidity of biodegradable polymers can be softened and their flexibility increased by a treatment with a known plastiziser, N-methyl-2-pyrrolidone (NMP), to an extent that allows their use in GBR. Additionally, it was found that NMP itself had an unexpected bone formation inducing effect.
New approaches in the utilization of the BMPs as well as in the application of biodegradable polymers as carriers in medicine are still needed.
The object of the present invention is to meet this need and provide new means to overcome the disadvantages and the drawbacks described above.
An object of the present invention is thus to provide novel means for the utilization of the bone forming inductive activity of the BMPs in the treatment of patients in dentistry, including periodontics, and in other fields in medicine, such as orthopedics.
Another object of the invention is to provide means, which afford a dose reduction of the BMPs, especially recombinantly produced BMPs, thereby allowing a safe and cost effective use of the BMPs in the treatment of patients in dentistry, including periodontics, and in other fields in medicine, such as orthopedics.
Still a further object of the invention is to provide new means for the use of guided bone regeneration (GBR).
Yet another object of the invention is to provide new means for the use of biodegradable membranes in GBR, whereby the second surgical stage can be avoided.
An object of the present invention is to provide pharmaceutical compositions, in which the bone morphogenetic properties of the BMPs together with the bone formation inducing properties of pyrrolidones, such as NMP, are utilized in synergistic manner, the compositions being useful in the treatment of dental and periodontal diseases, including the integration of dental implants and the filling of tooth sockets following extraction.
A further object of the present invention is to provide pharmaceutical compositions, in which the bone morphogenetic properties of the BMP together with the bone formation inducing properties of pyrrolidones, such as NMP, and biodegradable polymers are utilized in a synergistic manner, the compositions being useful in the treatment of dental and periodontal diseases, including the integration of dental implants and the filling of tooth sockets following extraction, specifically via guided bone regeneration (GBR).
Yet a further object of the present invention is to provide a method of treating a subject in a need of induction of bone formation, in which the bone morphogenetic properties of the BMP together with the bone formation inducing properties of pyrrolidones, such as NMP, and optionally biodegradable polymers are utilized in synergistic manner, to treat dental and periodontal diseases, including the integration of dental implants and the filling of tooth sockets following extraction, and to treat orthopedic diseases and failures, in which the enhancement of fracture healing and the augmentation of bone is desired, such as in the alveolar ridge augmentation, in the sinus floor elevation, and in the healing of non-unions, including improvement of the recovery of patients having a surgical bone operation or accidental bone fractures.